Sequential high throughput screening method and system

ABSTRACT

A method and system for high-throughput screening of multiphase reactions are provided. In an exemplary embodiment the method includes the steps of sequentially loading a plurality of discrete combinations of reactants into a longitudinal reaction zone; reacting each of the combinations as it passes through the reaction zone to provide a continuously or an incrementally varying reaction product; and sequentially discharging the reaction product of each of combination from the reaction zone as reaction of each combination is completed.

BACKGROUND

1. Field of the Invention

The present invention relates to a sequential high throughput screening (HTS) method and system.

2. Discussion of Related Art

In experimental reaction systems, each potential combination of reactant, catalyst and condition should be evaluated in a manner that provides correlation to performance in a production scale reactor. Combinatorial organic synthesis (COS) is an HTS methodology that was developed for pharmaceuticals. COS uses systematic and repetitive synthesis to produce diverse molecular entities formed from sets of chemical “building blocks.” As with traditional research, COS relies on experimental synthesis methodology. However instead of synthesizing a single compound, COS exploits automation and miniaturization to produce large libraries of compounds through successive stages, each of which produces a chemical modification of an existing molecule of a preceding stage. The procedure provides large libraries of diverse compounds that can be screened for various activities.

The techniques used to prepare such libraries involve a stepwise or sequential coupling of building blocks to form the compounds of interest. For example, Pirrung et al., U.S. Pat. No. 5,143,854 ostensibly discloses a technique for generating arrays of peptides and other molecules using, for example, light-directed, spatially-addressable synthesis techniques. Pirrung synthesized polypeptide arrays on a substrate by attaching photoremovable groups to the surface of the substrate, exposing selected regions of the substrate to light to activate those regions, attaching an amino acid monomer with a photoremovable group to the activated region, and repeating the steps of activation and attachment until polypeptides of the desired length and sequences are synthesized.

According to the teachings of Pirrung, each synthesis requires bringing the array to reaction conditions, which requires time. If multiple synthesis steps are utilized as is often the case, each synthesis step should be carefully controlled to achieve uniform reaction conditions and time. Uniform reaction conditions and time periods are difficult to achieve with batch processing of array plates. Further, it is difficult to define and control reaction time with batch processing, since each array plate must be individually “ramped” to target synthesis conditions and then “backed off” from the conditions upon completing the reaction. Considerable manual manipulation may be required at startup and shutdown in adjusting controls, loading samples and bolting enclosures.

Additionally, a high pressure reactor large enough to hold an array plate would require thick walls that cause a delay in controlling temperature. Adjustment of temperature within the reactor always lags behind adjustment at the temperature control. This can be a serious problem where precise temperature control is required. For example, catalyst reaction studies typically require temperature measurement and control to better than ±2° C. (preferably ±0.5° C.).

There is a need for an HTS method and system to easily conduct multiple syntheses under identical or precisely controlled variable conditions and reaction times.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed to a method and apparatus for rapid screening of multiphase reactant systems. In one exemplary embodiment, the method includes the steps of sequentially loading a plurality of discrete combinations of reactants into a longitudinal reaction zone; reacting each of the combinations as it passes through the reaction zone to provide a continuously or an incrementally varying reaction product; and sequentially discharging the reaction product of each of combination from the reaction zone as reaction of each combination is completed.

In another aspect, the present invention is directed to a combinatorial chemical synthesis system, comprising a vessel having a charge port adapted to sequentially receive a plurality of discrete combinations of reactants and a reaction chamber in communication with the charge port and adapted to receive and enclose the plurality of reactant combinations disposed linearly within the chamber. A discharge port is placed in communication with the reaction chamber to sequentially discharge reaction products from the reaction chamber.

BRIEF DESCRIPTION OF THE DRAWINGS

Various features, aspects, and advantages of the present invention will become more apparent with reference to the following description, appended claims, and accompanying drawings, wherein

FIG. 1 is a schematic representation of an aspect of an embodiment of the present invention;

FIG. 2 is a schematic representation of an aspect of an embodiment of the present invention;

FIG. 3 is a schematic representation of an aspect of an embodiment of the present invention;

FIG. 4 is a table of sequences for carrying out an aspect of an embodiment of the present invention; and.

FIG. 5 is a graph showing influence of effects and interactions utilizing an embodiment of the present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Various embodiments of the present system are capable of fully unattended around the clock operation. Temperature, pressure, reaction time and reactant mix within a vessel reaction chamber can be fully automated to allow complete experimentation within precisely scheduled parameters. Sequential high throughput screening (HTS) methods can be conducted within the tubular reactor. For example, sequentially loaded combinations of reactants can be subjected to a varying parameter of reaction within a reaction zone of the reactor to provide continuously or incrementally varying product. The composition of each sequentially loaded combination can be controlled along with control of varying parameters of reaction within the reaction zone and sequentially produced products can be detected by a convention detecting means. The detected products can be correlated with the varying parameters of the reaction to provide a nonrandom combinatorial library of product.

These and other features will become apparent from the drawings and following detailed discussion, which by way of example without limitation describes preferred embodiments of the present invention.

FIG. 1 is a schematic representation of an exemplary system 10 for sequential combinatorial chemical synthesis. FIG. 1 shows a system 10 including a sequential loader 12, a reaction vessel 14, a controller 16 and a detector 18. Loader 12 is shown having an encasement 20 enclosing an array 22 of vials 24 and a robotic frame 26 that includes an X-Y positioning arm 28 and an extendable vial manipulator 30.

Reaction vessel 14 and controller 16 are shown in more detail in FIG. 2. Referring to both FIG. 1 and FIG. 2, vessel 14 includes a longitudinal reaction chamber 32 having a charge pipe 34 at a chamber first end 36 and a mechanical exit actuator 38 and a discharge pipe 40 at a chamber second end 42. Charge pipe 34 includes a charge port 44 for receiving sequentially loaded vials 24 from loader 12. Charge pipe 34 provides a conveyance for receiving vials 24 and conveying the vials in a sequential fashion to reaction chamber 32. Charge pipe 34 is provided with at least two valves—a charge actuator 46 and a charge gas lock actuator 48—that create a charge gas lock zone 50. Similarly, discharge pipe 40 includes a discharge port 52 for discharging vials 24 that have been sequentially transported through discharge pipe 40 from reaction chamber 32. In the embodiment shown, discharge pipe 40 is provided with at least two valves—a discharge gas lock actuator 54 and a discharge actuator 56 that create a discharge gas-lock zone 58.

Further shown in FIG. 2 is a gas supply and valving combination that illustrates a preferred feature. A gas pressure generator 60 supplies high pressure gas via a pipe 62 to charge pipe 34 and via a pipe 64 to charge gas lock zone 50. Also, gas pressure generator 60 supplies high pressure gas via a pipe 66 to discharge gas lock zone 58. Pipe 62 includes a charge lock pressure valve 68 that regulates pressure within charge gas lock zone 50. Pipe 64 includes a vessel valve 70 that regulates pressure within reaction vessel 14. Pipe 66 includes a three way discharge lock pressure valve 72 that regulates pressure within discharge gas lock zone 58 by injecting gas or by releasing pressure via a vent 74 to the atmosphere.

The system can include a controller as shown in FIG. 1 and FIG. 2. Controller 16 includes a processor 76, which can be a microprocessor, computer or the like. Processor 76 can be controllably connected to any or all of charge actuator 46, charge lock pressure valve 68, charge gas lock actuator 48, vessel valve 70, mechanical exit actuator 38, discharge gas lock actuator 54, vessel valve 70, and discharge actuator 56 via lines 78, 80, 82, 84, 86, 88, and 90 to provide a controlled sequential combinatorial chemical synthesis as hereinafter described.

FIG. 1 shows a cut away side view of the reaction vessel 14 showing a stack of vials 24 progressing through longitudinal reaction chamber 32. FIG. 1 also shows an electronic heating jacket 102 encompassing chamber 32. FIG. 3 further shows jacket 102 in combination with a structure for controlling temperature conditions within the chamber 32. The structure includes insulation 104 interposed within jacket 102, a high precision temperature measuring device 106, and a feedback heat controller 108. Examples of the high precision temperature measuring device include a thermocouple, thermistor, or platinum resistance thermometer. Heat controller 108 is attached to the interior of chamber 32 by leads 110. Electronic heating jacket 102 is shown with feedback control via temperature measuring device 106, which can be a probe and heat controller 108. Other combinations can be used to control the temperature in chamber 32 such as a vapor heating jacket with pressure control, so long as the temperature can be controlled to within ±2° C., desirably within ±1° C. and preferably within ±0.5° C.

An HTS method can be conducted in the system shown in FIGS. 1, 2 and 3. In an exemplary embodiment of the method, an array of catalyst formulations is prepared according to any suitable procedure. For example, one procedure produces a homogeneous chemical reaction utilizing multiphase reactants. In this procedure, a formulation is prepared that represents a first reactant that is at least partially embodied in a liquid. During the subsequent reaction, the liquid of the first reactant can be contacted with a second reactant at least partially embodied in a gas. The liquid forms a film having a thickness sufficient to allow the reaction rate of the chemical reaction to be essentially independent of the mass transport rate of the second reactant into the liquid.

Each thin film formulation is deposited into a vial 24 to provide an array of reaction vials 24. Vial 24 is preferably formed of a rigid material that is chemically inert in the reaction environment. An example of an acceptable vial for many reactions is a glass vial. When dealing with liquids with low vapor pressures or with lengthy reactions, it may be desirable to provide a covering, such as a selectively permeable cap 16 or a septum (not shown) incorporating a feed tube or needle disposed such that a gas is allowed to move freely into and out of vial 24 while depletion of liquid by evaporation is minimized. This arrangement allows an external pressure source to act upon the gas in the reactant environment while evaporation of liquid is limited. In most applications, suitable materials for the cap include polytetrafluoroethylene (PTFE) and expanded PTFE. A suitable cap for use with 2 ml glass vials is “Clear Snap Cap, PTFE/Silicone/PTFE with Starburst, 11 mm”, part no. 27428, available from Supelco, Inc., Bellefonte, Pa.

The sequential loader 12 can be coordinated by controller 16 with a valving and actuator sequence described in the table of FIG. 4. With reference to FIG. 4, at commencement of operations, charge valve actuator 46 and discharge actuator 56 are open and the mechanical exit actuator 38 is deactivated (off); charge gas lock valve 46, charge lock pressure valve 68, vessel pressure valve 70 and discharge gas lock actuator 54 are closed and the three way gas lock valve 72 is in a vent position. The array of vials is positioned within sequential loader 12. Extendable X-Y positioning arm 28 grasps a vial 24 from the array 22 and positions the vial above charge port 44. Vessel pressure valve 70 is opened. A first vial from the array is charged by positioning arm 28 through open actuator 46 into charge gas lock zone 50 and the actuator is closed. Charge lock pressure valve 68 is opened and the charge lock zone 50 is pressurized to a pressure to match a reaction pressure within reaction chamber 32.

When pressure in charge lock zone 50 matches the reaction chamber pressure, charge lock pressure valve 68 is closed and charge gas lock actuator 48 is actuated to advance vial 24 into reaction chamber 32 and the actuator is closed. At this time, charge valve actuator 46 can be opened and charge gas lock zone 50 vented.

Vial contents are subjected to temperature and pressure reaction conditions within reaction chamber 32. Discharge actuator 56 is closed and three way discharge lock valve 72 is positioned to admit pressured gas from gas pressure generator 60 into discharge gas lock zone 58. Upon completion of reaction of the vial contents, mechanical exit actuator 38 is activated. Mechanical actuator 38 extends an arm immediately above vial 24 to prevent upper vials from dropping when a discharged vial drops from the chamber 32 into discharge gas lock zone 58. Discharge gas lock actuator 54 is then closed. Mechanical actuator 38 withdraws the arm, allowing vials above discharged vial 24 to drop so that the stack is now at the bottom of the tube.

Discharge gas lock zone 58 is depressurized by venting via three way valve 72 and discharge actuator 58 is opened to discharge vial 22 from zone 58 and thence from discharge pipe 40 to detector 18.

The above valve and actuator cycling procedure has been described with reference to processing of a single vial 22. However, a plurality of vials can be processed by repeating the FIG. 4 steps 2-8 a plurality of times to fill reaction chamber 32. Once chamber 32 is filled, then steps 2-16 are repeated to discharge a vial and to charge a vial to the reaction chamber.

Referring again to FIG. 1, the system also includes detector 18, which comprises a vial ejector 92 to direct a vial 24 from the reaction vessel discharge port 52 to a position within a vial array 94 that is retained on an X-Y positioning stage 96. The sequence of FIG. 4 can be coordinated with detector 18. Detector 18 further includes a fiber optic sensor 98 to sense the contents of the vials in combination with an analyzer 100. Analyzer 100 can utilize chromatography, infra red spectroscopy, mass spectroscopy, laser mass spectroscopy, microspectroscopy, NMR or the like to determine the constituency of each vial content.

In operation, X-Y positioning stage 96 of detector 18 positions an opening in array 94 directly beneath discharge port 52 so that when discharged, vial 24 falls cleanly into the array. Controller 16 registers the exact time a vial discharges from reactor vessel 14. X-Y positioning stage 96 moves array 94 beneath fiber optic sensor 98, which senses the contents of vial 24 for analysis by analyzer 100. For example, if the method and system of the invention is used to conduct a combinatorial synthesis to select a carbonylation catalyst and/or to determine optimum carbonylation reaction conditions, the analyzer analyzes the contents of the vial for carbonylated product. In this case, the analyzer can use Raman spectroscopy. The Raman peak is integrated using the analyzer electronics and the resulting data can be stored in the controller. Other analytical methods may be used as noted above.

The sequential combinatorial chemical synthesis herein described can be used with any suitable reactant system. For example, the system and method herein can be used for determining a method for producing diphenyl carbonate (DPC). Diphenyl carbonate (DPC) is useful, inter alia, as an intermediate in the preparation of polycarbonates. One method for producing DPC involves the carbonylation of a hydroxyaromatic compound (e.g., phenol) in the presence of a catalyst system. A carbonylation catalyst system typically includes a Group VIII B metal (e.g., palladium), a halide composition, and a combination of inorganic co-catalysts (IOCCs). This one step reaction is typically carried out in a continuous reactor at high temperature and pressure with gas sparging. Insufficient gas/liquid mixing can result in low yields of DPC. Generally, testing of new catalyst systems has been accomplished at macro-scale and, because the mechanism of this carbonylation reaction is not fully understood, the identity of additional effective IOCCs has eluded practitioners. An embodiment of the present invention allows this homogeneous carbonylation reaction to be carried out in parallel with various potential catalyst systems and, consequently, this embodiment can be used to identify effective IOCCs for the carbonylation of phenol.

The following example is provided in order that those skilled in the art will be better able to understand and practice the present invention. This example is intended to serve as an illustration and not as a limitation of the present invention as defined in the claims herein.

EXAMPLE

The economics of producing DPC by the above-mentioned carbonylation process is partially dependent on the number of moles of DPC produced per mole of Group VIII B metal utilized. In the following example, the Group VIII B metal utilized is palladium. For convenience, the number of moles of DPC produced per mole of palladium utilized is referred to as the palladium turnover number (Pd TON). Unless otherwise specified, all parts are by weight; all equivalents are relative to palladium; and all reactions are carried out in 2 ml glass vials at 90-100° C. in a 10% O₂ in CO atmosphere at an operating pressure of 95-110 atm. Reaction is generally 2-3 hours. Reaction products are verified by gas chromatography.

This example illustrates an identification of an active and selective catalyst for the production of aromatic carbonates. The procedure identifies the best catalyst from a complex chemical space, where the chemical space is defined as an assemblage of all possible experimental conditions defined by a set of variable parameters such as formulation ingredient identity or amount or process parameter such as reaction time, temperature, or pressure. In the Example, an initial iteration examines an experimental formulation consisting of six chemical species shown in TABLE 1 and the process parameters shown in TABLE 2. TABLE 1 Formulation Type Parameter Formulation Amount Variation Parameter Variation Precious Held Constant Held Constant metal catalyst Metal Fe, Cu, Ni, Pb, Re (as their 5, 20 (as molar ratios to Catalyst 1 (M1) acetylacetonates) precious metal catalyst) Metal V, W, Ce, La, Sn (as their 5, 20 (as molar ratios to Catalyst 2 (M2) acetylacetonates) precious metal catalyst) Cosolvent (CS) Dimethylformamide Varied independently in (DMFA), amount. Values are 500, Dimethylacetamide 4000 (as molar ratios to (DMAA), precious metal catalyst) Tetrahydrofuran (THF), Diglyme (DiGly), Diethylacetamide (DEAA) Hydroxyaromatic Held constant Sufficient added compound to achieve constant sample volume

TABLE 2 Process Parameter Process Parameter Variation Pressure 1000 psi, 1500 psi (8% Oxygen in Carbon Monoxide) Temperature 100 C., 120 C. Reaction Time 1 hour, 2 hours.

The size of the initial chemical space defined by the parameters of TABLE 1 and TABLE 2 is calculated as 8000 possibilities. This is a very large experiment for conventional techniques. In Iteration 1 of the process, a 400-sample subset of the 8000 possibilities is selected to screen formulation factors (M1, M2, and CS) while maintaining full representation of the quantity and process factors. A Latin Square design strategy is applied to generate a 5×5 square of the formulation factors. A Latin Square is an orthogonal design that allows each value of each factor to combine with each value of each other factor exactly once. In the present instance, the Latin Square is represented in abbreviated form in TABLE 3 and fully expanded in TABLE 4. TABLE 3 M1 Fe Cu Ni Pb Re M2 V DMFA DMAA THF DiGly DEAA W DMAA THF DiGly DEAA DMFA Ce THF DiGly DEAA DMFA DMAA La DiGly DEAA DMFA DMAA THF Sn DEAA DMFA DMAA THF DiGly

TABLE 4 M11 M12 Cosolvent TON Cu V DMFA 2158 Cu W DMAA 2873 Cu Ce THF 1519 Cu La DiGly 1416 Cu Sn DEAA 1336 Fe V DMAA 3695 Fe W THF 4012 Fe Ce DiGly 2983 Fe La DEAA 2882 Fe Sn DMFA 3034 Ni V THF 347 Ni W DiGly 1122 Ni Ce DEAA 154 Ni La DMFA 44 Ni Sn DMAA 252 Pb V DiGly 522 Pb W DEAA 1127 Pb Ce DMFA 102 Pb La DMAA 139 Pb Sn THF 49 Re V DEAA 492 Re W DMFA 1184 Re Ce DMAA 298 Re La THF 89 Re Sn DiGly 55

A 16-run 2-level fractional factorial design is generated in the six process variables. A 2-level fractional factorial design is an experiment with >1 adjustable control parameters (factors), each of which takes on 2 values (levels). All possible combinations of the factors and levels are generated. A fraction of the possible combinations is selected to maximize the value of information gained from the experiment. In this Example, six process variables generate 64 possibilities, of which one-fourth is selected according to the fractional factorial design. TABLE 5 shows the selected possibilities. TABLE 5 M1 amt M2 amp CS amt Pressure Temp Time 5.00 20.00 500.00 1000.00 120.00 2.00 20.00 5.00 500.00 1200.00 120.00 2.00 5.00 5.00 500.00 1000.00 100.00 1.00 5.00 5.00 500.00 1200.00 100.00 2.00 5.00 5.00 4000.00 1000.00 120.00 2.00 5.00 20.00 500.00 1200.00 120.00 1.00 5.00 20.00 4000.00 1200.00 100.00 2.00 5.00 5.00 4000.00 1200.00 120.00 1.00 20.00 20.00 500.00 1200.00 100.00 1.00 20.00 20.00 4000.00 1200.00 120.00 2.00 20.00 5.00 4000.00 1000.00 100.00 2.00 20.00 20.00 500.00 1000.00 100.00 2.00 5.00 20.00 4000.00 1000.00 100.00 1.00 20.00 5.00 4000.00 1200.00 100.00 1.00 20.00 20.00 4000.00 1000.00 120.00 1.00 20.00 5.00 500.00 1000.00 120.00 1.00

A composite design is then generated in which each run of the fractional factorial design is performed at each combination of the Latin Square, for a total of 25×16=400 samples. The composite design is sorted by pressure, temperature and time as shown in TABLE 6. TABLE 6 M1 M2 CS Sample M1 M2 CS amt amt amt Pressure Temp Time 1 Cu V DMFA 5 5 500 1000 100 1 2 Cu V DMFA 5 20 4000 1000 100 1 3 Cu W DMAA 5 5 500 1000 100 1 4 Cu W DMAA 5 20 4000 1000 100 1 5 Cu Ce THF 5 5 500 1000 100 1 6 Cu Ce THF 5 20 4000 1000 100 1 7 Cu La DiGly 5 5 500 1000 100 1 8 Cu La DiGly 5 20 4000 1000 100 1 9 Cu Sn DEAA 5 5 500 1000 100 1 10 Cu Sn DEAA 5 20 4000 1000 100 1 11 Fe V DMAA 5 5 500 1000 100 1 12 Fe V DMAA 5 20 4000 1000 100 1 13 Fe W THF 5 5 500 1000 100 1 14 Fe W THF 5 20 4000 1000 100 1 15 Fe Ce DiGly 5 5 500 1000 100 1 16 Fe Ce DiGly 5 20 4000 1000 100 1 17 Fe La DEAA 5 5 500 1000 100 1 18 Fe La DEAA 5 20 4000 1000 100 1 19 Fe Sn DMFA 5 5 500 1000 100 1 20 Fe Sn DMFA 5 20 4000 1000 100 1 21 Ni V THF 5 5 500 1000 100 1 22 Ni V THF 5 20 4000 1000 100 1 23 Ni W DiGly 5 5 500 1000 100 1 24 Ni W DiGly 5 20 4000 1000 100 1 25 Ni Ce DEAA 5 5 500 1000 100 1 26 Ni Ce DEAA 5 20 4000 1000 100 1 27 Ni La DMFA 5 5 500 1000 100 1 28 Ni La DMFA 5 20 4000 1000 100 1 29 Ni Sn DMAA 5 5 500 1000 100 1 30 Ni Sn DMAA 5 20 4000 1000 100 1 31 Pb V DiGly 5 5 500 1000 100 1 32 Pb V DiGly 5 20 4000 1000 100 1 33 Pb W DEAA 5 5 500 1000 100 1 34 Pb W DEAA 5 20 4000 1000 100 1 35 Pb Ce DMFA 5 5 500 1000 100 1 36 Pb Ce DMFA 5 20 4000 1000 100 1 37 Pb La DMAA 5 5 500 1000 100 1 38 Pb La DMAA 5 20 4000 1000 100 1 39 Pb Sn THF 5 5 500 1000 100 1 40 Pb Sn THF 5 20 4000 1000 100 1 41 Re V DEAA 5 5 500 1000 100 1 42 Re V DEAA 5 20 4000 1000 100 1 43 Re W DMFA 5 5 500 1000 100 1 44 Re W DMFA 5 20 4000 1000 100 1 45 Re Ce DMAA 5 5 500 1000 100 1 46 Re Ce DMAA 5 20 4000 1000 100 1 47 Re La THF 5 5 500 1000 100 1 48 Re La THF 5 20 4000 1000 100 1 49 Re Sn DiGly 5 5 500 1000 100 1 50 Re Sn DiGly 5 20 4000 1000 100 1 51 Cu V DMFA 20 5 4000 1000 100 2 52 Cu V DMFA 20 20 500 1000 100 2 53 Cu W DMAA 20 5 4000 1000 100 2 54 Cu W DMAA 20 20 500 1000 100 2 55 Cu Ce THF 20 5 4000 1000 100 2 56 Cu Ce THF 20 20 500 1000 100 2 57 Cu La DiGly 20 5 4000 1000 100 2 58 Cu La DiGly 20 20 500 1000 100 2 59 Cu Sn DEAA 20 5 4000 1000 100 2 60 Cu Sn DEAA 20 20 500 1000 100 2 61 Fe V DMAA 20 5 4000 1000 100 2 62 Fe V DMAA 20 20 500 1000 100 2 63 Fe W THF 20 5 4000 1000 100 2 64 Fe W THF 20 20 500 1000 100 2 65 Fe Ce DiGly 20 5 4000 1000 100 2 66 Fe Ce DiGly 20 20 500 1000 100 2 67 Fe La DEAA 20 5 4000 1000 100 2 68 Fe La DEAA 20 20 500 1000 100 2 69 Fe Sn DMFA 20 5 4000 1000 100 2 70 Fe Sn DMFA 20 20 500 1000 100 2 71 Ni V THF 20 5 4000 1000 100 2 72 Ni V THF 20 20 500 1000 100 2 73 Ni W DiGly 20 5 4000 1000 100 2 74 Ni W DiGly 20 20 500 1000 100 2 75 Ni Ce DEAA 20 5 4000 1000 100 2 76 Ni Ce DEAA 20 20 500 1000 100 2 77 Ni La DMFA 20 5 4000 1000 100 2 78 Ni La DMFA 20 20 500 1000 100 2 79 Ni Sn DMAA 20 5 4000 1000 100 2 80 Ni Sn DMAA 20 20 500 1000 100 2 81 Pb V DiGly 20 5 4000 1000 100 2 82 Pb V DiGly 20 20 500 1000 100 2 83 Pb W DEAA 20 5 4000 1000 100 2 84 Pb W DEAA 20 20 500 1000 100 2 85 Pb Ce DMFA 20 5 4000 1000 100 2 86 Pb Ce DMFA 20 20 500 1000 100 2 87 Pb La DMAA 20 5 4000 1000 100 2 88 Pb La DMAA 20 20 500 1000 100 2 89 Pb Sn THF 20 5 4000 1000 100 2 90 Pb Sn THF 20 20 500 1000 100 2 91 Re V DEAA 20 5 4000 1000 100 2 92 Re V DEAA 20 20 500 1000 100 2 93 Re W DMFA 20 5 4000 1000 100 2 94 Re W DMFA 20 20 500 1000 100 2 95 Re Ce DMAA 20 5 4000 1000 100 2 96 Re Ce DMAA 20 20 500 1000 100 2 97 Re La THF 20 5 4000 1000 100 2 98 Re La THF 20 20 500 1000 100 2 99 Re Sn DiGly 20 5 4000 1000 100 2 100 Re Sn DiGly 20 20 500 1000 100 2 101 Cu V DMFA 20 20 4000 1000 120 1 102 Cu V DMFA 20 5 500 1000 120 1 103 Cu W DMAA 20 20 4000 1000 120 1 104 Cu W DMAA 20 5 500 1000 120 1 105 Cu Ce THF 20 20 4000 1000 120 1 106 Cu Ce THF 20 5 500 1000 120 1 107 Cu La DiGly 20 20 4000 1000 120 1 108 Cu La DiGly 20 5 500 1000 120 1 109 Cu Sn DEAA 20 20 4000 1000 120 1 110 Cu Sn DEAA 20 5 500 1000 120 1 111 Fe V DMAA 20 20 4000 1000 120 1 112 Fe V DMAA 20 5 500 1000 120 1 113 Fe W THF 20 20 4000 1000 120 1 114 Fe W THF 20 5 500 1000 120 1 115 Fe Ce DiGly 20 20 4000 1000 120 1 116 Fe Ce DiGly 20 5 500 1000 120 1 117 Fe La DEAA 20 20 4000 1000 120 1 118 Fe La DEAA 20 5 500 1000 120 1 119 Fe Sn DMFA 20 20 4000 1000 120 1 120 Fe Sn DMFA 20 5 500 1000 120 1 121 Ni V THF 20 20 4000 1000 120 1 122 Ni V THF 20 5 500 1000 120 1 123 Ni W DiGly 20 20 4000 1000 120 1 124 Ni W DiGly 20 5 500 1000 120 1 125 Ni Ce DEAA 20 20 4000 1000 120 1 126 Ni Ce DEAA 20 5 500 1000 120 1 127 Ni La DMFA 20 20 4000 1000 120 1 128 Ni La DMFA 20 5 500 1000 120 1 129 Ni Sn DMAA 20 20 4000 1000 120 1 130 Ni Sn DMAA 20 5 500 1000 120 1 131 Pb V DiGly 20 20 4000 1000 120 1 132 Pb V DiGly 20 5 500 1000 120 1 133 Pb W DEAA 20 20 4000 1000 120 1 134 Pb W DEAA 20 5 500 1000 120 1 135 Pb Ce DMFA 20 20 4000 1000 120 1 136 Pb Ce DMFA 20 5 500 1000 120 1 137 Pb La DMAA 20 20 4000 1000 120 1 138 Pb La DMAA 20 5 500 1000 120 1 139 Pb Sn THF 20 20 4000 1000 120 1 140 Pb Sn THF 20 5 500 1000 120 1 141 Re V DEAA 20 20 4000 1000 120 1 142 Re V DEAA 20 5 500 1000 120 1 143 Re W DMFA 20 20 4000 1000 120 1 144 Re W DMFA 20 5 500 1000 120 1 145 Re Ce DMAA 20 20 4000 1000 120 1 146 Re Ce DMAA 20 5 500 1000 120 1 147 Re La THF 20 20 4000 1000 120 1 148 Re La THF 20 5 500 1000 120 1 149 Re Sn DiGly 20 20 4000 1000 120 1 150 Re Sn DiGly 20 5 500 1000 120 1 151 Cu V DMFA 5 20 500 1000 120 2 152 Cu V DMFA 5 5 4000 1000 120 2 153 Cu W DMAA 5 20 500 1000 120 2 154 Cu W DMAA 5 5 4000 1000 120 2 155 Cu Ce THF 5 20 500 1000 120 2 156 Cu Ce THF 5 5 4000 1000 120 2 157 Cu La DiGly 5 20 500 1000 120 2 158 Cu La DiGly 5 5 4000 1000 120 2 159 Cu Sn DEAA 5 20 500 1000 120 2 160 Cu Sn DEAA 5 5 4000 1000 120 2 161 Fe V DMAA 5 20 500 1000 120 2 162 Fe V DMAA 5 5 4000 1000 120 2 163 Fe W THF 5 20 500 1000 120 2 164 Fe W THF 5 5 4000 1000 120 2 165 Fe Ce DiGly 5 20 500 1000 120 2 166 Fe Ce DiGly 5 5 4000 1000 120 2 167 Fe La DEAA 5 20 500 1000 120 2 168 Fe La DEAA 5 5 4000 1000 120 2 169 Fe Sn DMFA 5 20 500 1000 120 2 170 Fe Sn DMFA 5 5 4000 1000 120 2 171 Ni V THF 5 20 500 1000 120 2 172 Ni V THF 5 5 4000 1000 120 2 173 Ni W DiGly 5 20 500 1000 120 2 174 Ni W DiGly 5 5 4000 1000 120 2 175 Ni Ce DEAA 5 20 500 1000 120 2 176 Ni Ce DEAA 5 5 4000 1000 120 2 177 Ni La DMFA 5 20 500 1000 120 2 178 Ni La DMFA 5 5 4000 1000 120 2 179 Ni Sn DMAA 5 20 500 1000 120 2 180 Ni Sn DMAA 5 5 4000 1000 120 2 181 Pb V DiGly 5 20 500 1000 120 2 182 Pb V DiGly 5 5 4000 1000 120 2 183 Pb W DEAA 5 20 500 1000 120 2 184 Pb W DEAA 5 5 4000 1000 120 2 185 Pb Ce DMFA 5 20 500 1000 120 2 186 Pb Ce DMFA 5 5 4000 1000 120 2 187 Pb La DMAA 5 20 500 1000 120 2 188 Pb La DMAA 5 5 4000 1000 120 2 189 Pb Sn THF 5 20 500 1000 120 2 190 Pb Sn THF 5 5 4000 1000 120 2 191 Re V DEAA 5 20 500 1000 120 2 192 Re V DEAA 5 5 4000 1000 120 2 193 Re W DMFA 5 20 500 1000 120 2 194 Re W DMFA 5 5 4000 1000 120 2 195 Re Ce DMAA 5 20 500 1000 120 2 196 Re Ce DMAA 5 5 4000 1000 120 2 197 Re La THF 5 20 500 1000 120 2 198 Re La THF 5 5 4000 1000 120 2 199 Re Sn DiGly 5 20 500 1000 120 2 200 Re Sn DiGly 5 5 4000 1000 120 2 201 Cu V DMFA 20 20 500 1200 100 1 202 Cu V DMFA 20 5 4000 1200 100 1 203 Cu W DMAA 20 20 500 1200 100 1 204 Cu W DMAA 20 5 4000 1200 100 1 205 Cu Ce THF 20 20 500 1200 100 1 206 Cu Ce THF 20 5 4000 1200 100 1 207 Cu La DiGly 20 20 500 1200 100 1 208 Cu La DiGly 20 5 4000 1200 100 1 209 Cu Sn DEAA 20 20 500 1200 100 1 210 Cu Sn DEAA 20 5 4000 1200 100 1 211 Fe V DMAA 20 20 500 1200 100 1 212 Fe V DMAA 20 5 4000 1200 100 1 213 Fe W THF 20 20 500 1200 100 1 214 Fe W THF 20 5 4000 1200 100 1 215 Fe Ce DiGly 20 20 500 1200 100 1 216 Fe Ce DiGly 20 5 4000 1200 100 1 217 Fe La DEAA 20 20 500 1200 100 1 218 Fe La DEAA 20 5 4000 1200 100 1 219 Fe Sn DMFA 20 20 500 1200 100 1 220 Fe Sn DMFA 20 5 4000 1200 100 1 221 Ni V THF 20 20 500 1200 100 1 222 Ni V THF 20 5 4000 1200 100 1 223 Ni W DiGly 20 20 500 1200 100 1 224 Ni W DiGly 20 5 4000 1200 100 1 225 Ni Ce DEAA 20 20 500 1200 100 1 226 Ni Ce DEAA 20 5 4000 1200 100 1 227 Ni La DMFA 20 20 500 1200 100 1 228 Ni La DMFA 20 5 4000 1200 100 1 229 Ni Sn DMAA 20 20 500 1200 100 1 230 Ni Sn DMAA 20 5 4000 1200 100 1 231 Pb V DiGly 20 20 500 1200 100 1 232 Pb V DiGly 20 5 4000 1200 100 1 233 Pb W DEAA 20 20 500 1200 100 1 234 Pb W DEAA 20 5 4000 1200 100 1 235 Pb Ce DMFA 20 20 500 1200 100 1 236 Pb Ce DMFA 20 5 4000 1200 100 1 237 Pb La DMAA 20 20 500 1200 100 1 238 Pb La DMAA 20 5 4000 1200 100 1 239 Pb Sn THF 20 20 500 1200 100 1 240 Pb Sn THF 20 5 4000 1200 100 1 241 Re V DEAA 20 20 500 1200 100 1 242 Re V DEAA 20 5 4000 1200 100 1 243 Re W DMFA 20 20 500 1200 100 1 244 Re W DMFA 20 5 4000 1200 100 1 245 Re Ce DMAA 20 20 500 1200 100 1 246 Re Ce DMAA 20 5 4000 1200 100 1 247 Re La THF 20 20 500 1200 100 1 248 Re La THF 20 5 4000 1200 100 1 249 Re Sn DiGly 20 20 500 1200 100 1 250 Re Sn DiGly 20 5 4000 1200 100 1 251 Cu V DMFA 5 5 500 1200 100 2 252 Cu V DMFA 5 20 4000 1200 100 2 253 Cu W DMAA 5 5 500 1200 100 2 254 Cu W DMAA 5 20 4000 1200 100 2 255 Cu Ce THF 5 5 500 1200 100 2 256 Cu Ce THF 5 20 4000 1200 100 2 257 Cu La DiGly 5 5 500 1200 100 2 258 Cu La DiGly 5 20 4000 1200 100 2 259 Cu Sn DEAA 5 5 500 1200 100 2 260 Cu Sn DEAA 5 20 4000 1200 100 2 261 Fe V DMAA 5 5 500 1200 100 2 262 Fe V DMAA 5 20 4000 1200 100 2 263 Fe W THF 5 5 500 1200 100 2 264 Fe W THF 5 20 4000 1200 100 2 265 Fe Ce DiGly 5 5 500 1200 100 2 266 Fe Ce DiGly 5 20 4000 1200 100 2 267 Fe La DEAA 5 5 500 1200 100 2 268 Fe La DEAA 5 20 4000 1200 100 2 269 Fe Sn DMFA 5 5 500 1200 100 2 270 Fe Sn DMFA 5 20 4000 1200 100 2 271 Ni V THF 5 5 500 1200 100 2 272 Ni V THF 5 20 4000 1200 100 2 273 Ni W DiGly 5 5 500 1200 100 2 274 Ni W DiGly 5 20 4000 1200 100 2 275 Ni Ce DEAA 5 5 500 1200 100 2 276 Ni Ce DEAA 5 20 4000 1200 100 2 277 Ni La DMFA 5 5 500 1200 100 2 278 Ni La DMFA 5 20 4000 1200 100 2 279 Ni Sn DMAA 5 5 500 1200 100 2 280 Ni Sn DMAA 5 20 4000 1200 100 2 281 Pb V DiGly 5 5 500 1200 100 2 282 Pb V DiGly 5 20 4000 1200 100 2 283 Pb W DEAA 5 5 500 1200 100 2 284 Pb W DEAA 5 20 4000 1200 100 2 285 Pb Ce DMFA 5 5 500 1200 100 2 286 Pb Ce DMFA 5 20 4000 1200 100 2 287 Pb La DMAA 5 5 500 1200 100 2 288 Pb La DMAA 5 20 4000 1200 100 2 289 Pb Sn THF 5 5 500 1200 100 2 290 Pb Sn THF 5 20 4000 1200 100 2 291 Re V DEAA 5 5 500 1200 100 2 292 Re V DEAA 5 20 4000 1200 100 2 293 Re W DMFA 5 5 500 1200 100 2 294 Re W DMFA 5 20 4000 1200 100 2 295 Re Ce DMAA 5 5 500 1200 100 2 296 Re Ce DMAA 5 20 4000 1200 100 2 297 Re La THF 5 5 500 1200 100 2 298 Re La THF 5 20 4000 1200 100 2 299 Re Sn DiGly 5 5 500 1200 100 2 300 Re Sn DiGly 5 20 4000 1200 100 2 301 Cu V DMFA 5 20 500 1200 120 1 302 Cu V DMFA 5 5 4000 1200 120 1 303 Cu W DMAA 5 20 500 1200 120 1 304 Cu W DMAA 5 5 4000 1200 120 1 305 Cu Ce THF 5 20 500 1200 120 1 306 Cu Ce THF 5 5 4000 1200 120 1 307 Cu La DiGly 5 20 500 1200 120 1 308 Cu La DiGly 5 5 4000 1200 120 1 309 Cu Sn DEAA 5 20 500 1200 120 1 310 Cu Sn DEAA 5 5 4000 1200 120 1 311 Fe V DMAA 5 20 500 1200 120 1 312 Fe V DMAA 5 5 4000 1200 120 1 313 Fe W THF 5 20 500 1200 120 1 314 Fe W THF 5 5 4000 1200 120 1 315 Fe Ce DiGly 5 20 500 1200 120 1 316 Fe Ce DiGly 5 5 4000 1200 120 1 317 Fe La DEAA 5 20 500 1200 120 1 318 Fe La DEAA 5 5 4000 1200 120 1 319 Fe Sn DMFA 5 20 500 1200 120 1 320 Fe Sn DMFA 5 5 4000 1200 120 1 321 Ni V THF 5 20 500 1200 120 1 322 Ni V THF 5 5 4000 1200 120 1 323 Ni W DiGly 5 20 500 1200 120 1 324 Ni W DiGly 5 5 4000 1200 120 1 325 Ni Ce DEAA 5 20 500 1200 120 1 326 Ni Ce DEAA 5 5 4000 1200 120 1 327 Ni La DMFA 5 20 500 1200 120 1 328 Ni La DMFA 5 5 4000 1200 120 1 329 Ni Sn DMAA 5 20 500 1200 120 1 330 Ni Sn DMAA 5 5 4000 1200 120 1 331 Pb V DiGly 5 20 500 1200 120 1 332 Pb V DiGly 5 5 4000 1200 120 1 333 Pb W DEAA 5 20 500 1200 120 1 334 Pb W DEAA 5 5 4000 1200 120 1 335 Pb Ce DMFA 5 20 500 1200 120 1 336 Pb Ce DMFA 5 5 4000 1200 120 1 337 Pb La DMAA 5 20 500 1200 120 1 338 Pb La DMAA 5 5 4000 1200 120 1 339 Pb Sn THF 5 20 500 1200 120 1 340 Pb Sn THF 5 5 4000 1200 120 1 341 Re V DEAA 5 20 500 1200 120 1 342 Re V DEAA 5 5 4000 1200 120 1 343 Re W DMFA 5 20 500 1200 120 1 344 Re W DMFA 5 5 4000 1200 120 1 345 Re Ce DMAA 5 20 500 1200 120 1 346 Re Ce DMAA 5 5 4000 1200 120 1 347 Re La THF 5 20 500 1200 120 1 348 Re La THF 5 5 4000 1200 120 1 349 Re Sn DiGly 5 20 500 1200 120 1 350 Re Sn DiGly 5 5 4000 1200 120 1 351 Cu V DMFA 20 5 500 1200 120 2 352 Cu V DMFA 20 20 4000 1200 120 2 353 Cu W DMAA 20 5 500 1200 120 2 354 Cu W DMAA 20 20 4000 1200 120 2 355 Cu Ce THF 20 5 500 1200 120 2 356 Cu Ce THF 20 20 4000 1200 120 2 357 Cu La DiGly 20 5 500 1200 120 2 358 Cu La DiGly 20 20 4000 1200 120 2 359 Cu Sn DEAA 20 5 500 1200 120 2 360 Cu Sn DEAA 20 20 4000 1200 120 2 361 Fe V DMAA 20 5 500 1200 120 2 362 Fe V DMAA 20 20 4000 1200 120 2 363 Fe W THF 20 5 500 1200 120 2 364 Fe W THF 20 20 4000 1200 120 2 365 Fe Ce DiGly 20 5 500 1200 120 2 366 Fe Ce DiGly 20 20 4000 1200 120 2 367 Fe La DEAA 20 5 500 1200 120 2 368 Fe La DEAA 20 20 4000 1200 120 2 369 Fe Sn DMFA 20 5 500 1200 120 2 370 Fe Sn DMFA 20 20 4000 1200 120 2 371 Ni V THF 20 5 500 1200 120 2 372 Ni V THF 20 20 4000 1200 120 2 373 Ni W DiGly 20 5 500 1200 120 2 374 Ni W DiGly 20 20 4000 1200 120 2 375 Ni Ce DEAA 20 5 500 1200 120 2 376 Ni Ce DEAA 20 20 4000 1200 120 2 377 Ni La DMFA 20 5 500 1200 120 2 378 Ni La DMFA 20 20 4000 1200 120 2 379 Ni Sn DMAA 20 5 500 1200 120 2 380 Ni Sn DMAA 20 20 4000 1200 120 2 381 Pb V DiGly 20 5 500 1200 120 2 382 Pb V DiGly 20 20 4000 1200 120 2 383 Pb W DEAA 20 5 500 1200 120 2 384 Pb W DEAA 20 20 4000 1200 120 2 385 Pb Ce DMFA 20 5 500 1200 120 2 386 Pb Ce DMFA 20 20 4000 1200 120 2 387 Pb La DMAA 20 5 500 1200 120 2 388 Pb La DMAA 20 20 4000 1200 120 2 389 Pb Sn THF 20 5 500 1200 120 2 390 Pb Sn THF 20 20 4000 1200 120 2 391 Re V DEAA 20 5 500 1200 120 2 392 Re V DEAA 20 20 4000 1200 120 2 393 Re W DMFA 20 5 500 1200 120 2 394 Re W DMFA 20 20 4000 1200 120 2 395 Re Ce DMAA 20 5 500 1200 120 2 396 Re Ce DMAA 20 20 4000 1200 120 2 397 Re La THF 20 5 500 1200 120 2 398 Re La THF 20 20 4000 1200 120 2 399 Re Sn DiGly 20 5 500 1200 120 2 400 Re Sn DiGly 20 20 4000 1200 120 2

In this evaluation, each of the metal acetylacetonates, the DMAA, and the DMFA is made up as a stock solution in phenol. An appropriate quantity of each stock solution is then combined using a Hamilton MicroLab 4000 laboratory robot into a single vial for mixing. For example, the stock solutions to produce vials 1, 65, 129, 193, 257, 321, 385, and 449, are 0.01 molar Pd (acetylacetonate), 0.01 molar each of Fe (acetylacetonate) and V (acetylacetonate) and 5 molar DMFA. Ten ml of each stock solution is produced by manual weighing and mixing. Aliquots of the stock solutions are measured as follows in TABLE 7. The mixture is stirred using a miniature magnetic stirrer, and then 25 microliters are measured out to each of eight 2-ml vials using the Hamilton robot. This small quantity forms a thin film on the vial bottom. TABLE 7 0.01 molar Pd(acetylacetonate)  25 microliters 0.01 molar Fe(acetylacetonate) 125 microliters 0.01 molar V(acetylacetonate) 125 microliters   5 molar DMFA  25 microliters Pure Phenol 700 microliters

After each mixture is made, mixed, and distributed to 2-ml vials, the vials are capped using “star” caps (which allow gas exchange with the environment) and placed in the loader of FIG. 1. The tubular reactor system is heated and pressurized to the conditions shown as Block 1 in TABLE 8 and the automatic loading and processing procedure discussed above is begun. Loading and unloading times are controlled so that each vial is in the heated reaction zone for the time shown in Block 1: 1 hour. The reaction zone can accommodate a stack of 20 vials. A new vial is added every three minutes until the stack is full, then one vial is removed and another added every three minutes thereafter. As vials progress down the stack, their exposure time is 20×3 minutes 60 minutes=1 hour. TABLE 8 Block Pressure (psi) Temperature (° C.) Time (hours) 1 1000 100 1 2 1000 100 2 3 1000 120 1 4 1000 120 2 5 1200 100 1 6 1200 100 2 7 1200 120 1 8 1200 120 2

As each vial exits the reactor, it falls into a new array and is analyzed by gas-liquid chromatography.

Performance is expressed numerically as a catalyst turnover number or TON. TON is defined as the number of moles of aromatic carbonate produced per mole of Palladium catalyst charged.

When all rows with the same pressure, temperature and reaction time have been processed, the pressure and temperature are adjusted to new conditions. The timing is adjusted and a next row is processed. This iteration is repeated until all conditions have been run. The performance of each vial is given in the column “TON” of TABLE 4. The TON's of TABLE 4 are averaged by each formulation component to give the results shown in TABLE 9. TAB:LE 9 shows that average TON is significantly larger for M1=Fe or Cu; M2=V or W; and cosolvent=DMFA or DMAA. These are selected for a second iteration. TABLE 9 M1 M1 ave M2 M2 ave Cosolvent CS ave Cu 1860.3 V 1442.8 DMFA 1304.4 Fe 3321.5 W 2063.5 DMAA 1451.5 Ni 383.8 Ce 1011.2 THF 1203.1 Pb 387.7 La 914.1 DiGly 1219.5 Re 423.7 Sn 945.3 DEAA 1198.4

In the second iteration of the process, experimental formulations consist of six chemical species shown in TABLE 10. Process parameters are shown in TABLE 11. TABLE 10 Formulation Type Formulation Amount Parameter Variation Parameter Variation Precious metal catalyst Held Constant Held Constant Metal Catalyst 1 (M1) Fe or Cu (as their 5, 20 (as molar ratios to acetylacetonates) precious metal catalyst) Metal Catalyst 2 (M2) V or W (as their 5, 20 (as molar ratios to acetylacetonates) precious metal catalyst) Cosolvent (CS) Dimethylformamide Varied independently in (DMFA) or amount. Possible values Dimethylacetamide were 500, 4000 (as molar (DMAA) ratios to precious metal catalyst) Hydroxyaromatic Held constant Sufficient added to achieve compound constant sample volume

TABLE 11 Process Parameter Process Parameter Variation Pressure 1000 psi, 1500 psi (8% Oxygen in Carbon Monoxide) Temperature 100 C., 120 C. Reaction Time 1 hour, 2 hours

Size of an initial chemical space defined by the parameters of TABLE 10 and TABLE 11 is calculated as 512 possibilities. The 512 possibilities are organized into an experiment of the type known as a “full factorial design” with pressure, temperature, and reaction time parameters “blocked.” A full factorial design is an experiment with >1 adjustable control parameters (factors) each of which can take on >1 value (levels). In a full factorial design experiment, an observation is taken at each of all possible combinations of levels that can be formed from the different factors. A full factorial design is capable of estimating all possible effects of the factors, including main effects and all interactions. The design is necessary where the intention of an experiment is to determine if there are unusual interactions, particularly between process and formulation variables. Where factors are “blocked,” factors that are relatively difficult to quickly vary are grouped together. A full factorial design for the chemical space of this Example is shown in TABLE 12. Block M1 M1 amt M2 M2 amt CS CS amt Pressure Temperature Time TON 1 Fe 5 V 5 DMFA 500 1000 100 1 1693.92 1 Cu 5 V 5 DMFA 500 1000 100 1 4091.21 1 Fe 20 V 5 DMFA 500 1000 100 1 1845.361 1 Cu 20 V 5 DMFA 500 1000 100 1 4038.68 1 Fe 5 W 5 DMFA 500 1000 100 1 1754.727 1 Cu 5 W 5 DMFA 500 1000 100 1 3956.726 1 Fe 20 W 5 DMFA 500 1000 100 1 1903.599 1 Cu 20 W 5 DMFA 500 1000 100 1 3676.381 1 Fe 5 V 20 DMFA 500 1000 100 1 2237.44 1 Cu 5 V 20 DMFA 500 1000 100 1 4171.727 1 Fe 20 V 20 DMFA 500 1000 100 1 2665.677 1 Cu 20 V 20 DMFA 500 1000 100 1 4063.274 1 Fe 5 W 20 DMFA 500 1000 100 1 1741.315 1 Cu 5 W 20 DMFA 500 1000 100 1 4263.502 1 Fe 20 W 20 DMFA 500 1000 100 1 2264.471 1 Cu 20 W 20 DMFA 500 1000 100 1 3990.751 1 Fe 5 V 5 DMAA 500 1000 100 1 1862.09 1 Cu 5 V 5 DMAA 500 1000 100 1 4000.029 1 Fe 20 V 5 DMAA 500 1000 100 1 1905.142 1 Cu 20 V 5 DMAA 500 1000 100 1 4195.94 1 Fe 5 W 5 DMAA 500 1000 100 1 2160.141 1 Cu 5 W 5 DMAA 500 1000 100 1 4556.547 1 Fe 20 W 5 DMAA 500 1000 100 1 2219.635 1 Cu 20 W 5 DMAA 500 1000 100 1 3939.92 1 Fe 5 V 20 DMAA 500 1000 100 1 2084.011 1 Cu 5 V 20 DMAA 500 1000 100 1 4214.699 1 Fe 20 V 20 DMAA 500 1000 100 1 2043.003 1 Cu 20 V 20 DMAA 500 1000 100 1 3939.684 1 Fe 5 W 20 DMAA 500 1000 100 1 1659.084 1 Cu 5 W 20 DMAA 500 1000 100 1 3834.039 1 Fe 20 W 20 DMAA 500 1000 100 1 1840.703 1 Cu 20 W 20 DMAA 500 1000 100 1 4183.744 1 Fe 5 V 5 DMFA 4000 1000 100 1 4451.489 1 Cu 5 V 5 DMFA 4000 1000 100 1 2199.05 1 Fe 20 V 5 DMFA 4000 1000 100 1 4345.231 1 Cu 20 V 5 DMFA 4000 1000 100 1 2177.339 1 Fe 5 W 5 DMFA 4000 1000 100 1 4439.784 1 Cu 5 W 5 DMFA 4000 1000 100 1 1915.281 1 Fe 20 W 5 DMFA 4000 1000 100 1 3416.777 1 Cu 20 W 5 DMFA 4000 1000 100 1 1906.395 1 Fe 5 V 20 DMFA 4000 1000 100 1 3955.658 1 Cu 5 V 20 DMFA 4000 1000 100 1 2068.799 1 Fe 20 V 20 DMFA 4000 1000 100 1 3757.099 1 Cu 20 V 20 DMFA 4000 1000 100 1 2195.421 1 Fe 5 W 20 DMFA 4000 1000 100 1 4265.04 1 Cu 5 W 20 DMFA 4000 1000 100 1 2622.194 1 Fe 20 W 20 DMFA 4000 1000 100 1 4080.135 1 Cu 20 W 20 DMFA 4000 1000 100 1 2165.103 1 Fe 5 V 5 DMAA 4000 1000 100 1 3917.162 1 Cu 5 V 5 DMAA 4000 1000 100 1 2401.285 1 Fe 20 V 5 DMAA 4000 1000 100 1 3756.023 1 Cu 20 V 5 DMAA 4000 1000 100 1 1860.372 1 Fe 5 W 5 DMAA 4000 1000 100 1 3812.629 1 Cu 5 W 5 DMAA 4000 1000 100 1 1539.843 1 Fe 20 W 5 DMAA 4000 1000 100 1 4062.504 1 Cu 20 W 5 DMAA 4000 1000 100 1 2322.649 1 Fe 5 V 20 DMAA 4000 1000 100 1 4085.449 1 Cu 5 V 20 DMAA 4000 1000 100 1 1662.921 1 Fe 20 V 20 DMAA 4000 1000 100 1 4030.069 1 Cu 20 V 20 DMAA 4000 1000 100 1 2271.779 1 Fe 5 W 20 DMAA 4000 1000 100 1 4267.062 1 Cu 5 W 20 DMAA 4000 1000 100 1 2020.112 1 Fe 20 W 20 DMAA 4000 1000 100 1 4066.339 1 Cu 20 W 20 DMAA 4000 1000 100 1 1900.791 2 Fe 5 V 5 DMFA 500 1000 100 2 3700.711 2 Cu 5 V 5 DMFA 500 1000 100 2 5105.03 2 Fe 20 V 5 DMFA 500 1000 100 2 3043.119 2 Cu 20 V 5 DMFA 500 1000 100 2 4908.279 2 Fe 5 W 5 DMFA 500 1000 100 2 2899.673 2 Cu 5 W 5 DMFA 500 1000 100 2 4806.417 2 Fe 20 W 5 DMFA 500 1000 100 2 3321.028 2 Cu 20 W 5 DMFA 500 1000 100 2 5529.844 2 Fe 5 V 20 DMFA 500 1000 100 2 3145.139 2 Cu 5 V 20 DMFA 500 1000 100 2 5495.893 2 Fe 20 V 20 DMFA 500 1000 100 2 2599.752 2 Cu 20 V 20 DMFA 500 1000 100 2 4521.231 2 Fe 5 W 20 DMFA 500 1000 100 2 3139.919 2 Cu 5 W 20 DMFA 500 1000 100 2 5106.096 2 Fe 20 W 20 DMFA 500 1000 100 2 3252.493 2 Cu 20 W 20 DMFA 500 1000 100 2 5025.739 2 Fe 5 V 5 DMAA 500 1000 100 2 2801.16 2 Cu 5 V 5 DMAA 500 1000 100 2 5625.641 2 Fe 20 V 5 DMAA 500 1000 100 2 2995.132 2 Cu 20 V 5 DMAA 500 1000 100 2 4854.658 2 Fe 5 W 5 DMAA 500 1000 100 2 2743.656 2 Cu 5 W 5 DMAA 500 1000 100 2 4617.833 2 Fe 20 W 5 DMAA 500 1000 100 2 3023.491 2 Cu 20 W 5 DMAA 500 1000 100 2 5087.621 2 Fe 5 V 20 DMAA 500 1000 100 2 3259.962 2 Cu 5 V 20 DMAA 500 1000 100 2 5375.063 2 Fe 20 V 20 DMAA 500 1000 100 2 2816.106 2 Cu 20 V 20 DMAA 500 1000 100 2 4596.62 2 Fe 5 W 20 DMAA 500 1000 100 2 3301.399 2 Cu 5 W 20 DMAA 500 1000 100 2 5095.495 2 Fe 20 W 20 DMAA 500 1000 100 2 3062.839 2 Cu 20 W 20 DMAA 500 1000 100 2 4980.406 2 Fe 5 V 5 DMFA 4000 1000 100 2 5301.676 2 Cu 5 V 5 DMFA 4000 1000 100 2 2992.894 2 Fe 20 V 5 DMFA 4000 1000 100 2 5226.527 2 Cu 20 V 5 DMFA 4000 1000 100 2 3229.047 2 Fe 5 W 5 DMFA 4000 1000 100 2 4741.478 2 Cu 5 W 5 DMFA 4000 1000 100 2 3150.125 2 Fe 20 W 5 DMFA 4000 1000 100 2 4602.754 2 Cu 20 W 5 DMFA 4000 1000 100 2 2719.743 2 Fe 5 V 20 DMFA 4000 1000 100 2 5004.734 2 Cu 5 V 20 DMFA 4000 1000 100 2 3115.677 2 Fe 20 V 20 DMFA 4000 1000 100 2 4969.642 2 Cu 20 V 20 DMFA 4000 1000 100 2 2806.752 2 Fe 5 W 20 DMFA 4000 1000 100 2 4879.942 2 Cu 5 W 20 DMFA 4000 1000 100 2 2891.03 2 Fe 20 W 20 DMFA 4000 1000 100 2 4912.866 2 Cu 20 W 20 DMFA 4000 1000 100 2 3036.185 2 Fe 5 V 5 DMAA 4000 1000 100 2 4437.605 2 Cu 5 V 5 DMAA 4000 1000 100 2 2880.5 2 Fe 20 V 5 DMAA 4000 1000 100 2 5043.313 2 Cu 20 V 5 DMAA 4000 1000 100 2 2875.502 2 Fe 5 W 5 DMAA 4000 1000 100 2 4705.449 2 Cu 5 W 5 DMAA 4000 1000 100 2 3012.273 2 Fe 20 W 5 DMAA 4000 1000 100 2 5032.286 2 Cu 20 W 5 DMAA 4000 1000 100 2 2658.891 2 Fe 5 V 20 DMAA 4000 1000 100 2 4690.863 2 Cu 5 V 20 DMAA 4000 1000 100 2 2695.653 2 Fe 20 V 20 DMAA 4000 1000 100 2 5029.318 2 Cu 20 V 20 DMAA 4000 1000 100 2 2964.375 2 Fe 5 W 20 DMAA 4000 1000 100 2 4540.673 2 Cu 5 W 20 DMAA 4000 1000 100 2 2848.039 2 Fe 20 W 20 DMAA 4000 1000 100 2 4994.425 2 Cu 20 W 20 DMAA 4000 1000 100 2 3097.556 3 Fe 5 V 5 DMFA 500 1000 120 1 3096.222 3 Cu 5 V 5 DMFA 500 1000 120 1 1130.108 3 Fe 20 V 5 DMFA 500 1000 120 1 3223.721 3 Cu 20 V 5 DMFA 500 1000 120 1 1391.525 3 Fe 5 W 5 DMFA 500 1000 120 1 3367.514 3 Cu 5 W 5 DMFA 500 1000 120 1 735.8303 3 Fe 20 W 5 DMFA 500 1000 120 1 3063.38 3 Cu 20 W 5 DMFA 500 1000 120 1 1264.4 3 Fe 5 V 20 DMFA 500 1000 120 1 3286.707 3 Cu 5 V 20 DMFA 500 1000 120 1 1162.79 3 Fe 20 V 20 DMFA 500 1000 120 1 3153.402 3 Fe 20 W 20 DMFA 4000 1000 120 1 1286.159 3 Cu 20 W 20 DMFA 4000 1000 120 1 3052.865 3 Fe 5 V 5 DMAA 4000 1000 120 1 1140.058 3 Cu 5 V 5 DMAA 4000 1000 120 1 2545.555 3 Fe 20 V 5 DMAA 4000 1000 120 1 1075.588 3 Cu 20 V 5 DMAA 4000 1000 120 1 3170.971 3 Fe 5 W 5 DMAA 4000 1000 120 1 1025.795 3 Cu 5 W 5 DMAA 4000 1000 120 1 3205.365 3 Fe 20 W 5 DMAA 4000 1000 120 1 1144.007 3 Cu 20 W 5 DMAA 4000 1000 120 1 3073.614 3 Fe 5 V 20 DMAA 4000 1000 120 1 991.2687 3 Cu 5 V 20 DMAA 4000 1000 120 1 2875.273 3 Fe 20 V 20 DMAA 4000 1000 120 1 987.423 3 Cu 20 V 20 DMAA 4000 1000 120 1 3169.661 3 Fe 5 W 20 DMAA 4000 1000 120 1 1393.893 3 Cu 5 W 20 DMAA 4000 1000 120 1 3361.081 3 Fe 20 W 20 DMAA 4000 1000 120 1 1464.002 3 Cu 20 W 20 DMAA 4000 1000 120 1 3221.897 4 Fe 5 V 5 DMFA 500 1000 120 2 3562.027 4 Cu 5 V 5 DMFA 500 1000 120 2 1169.025 4 Fe 20 V 5 DMFA 500 1000 120 2 3065.418 4 Cu 20 V 5 DMFA 500 1000 120 2 1179.965 4 Fe 5 W 5 DMFA 500 1000 120 2 3167.984 4 Cu 5 W 5 DMFA 500 1000 120 2 1297.288 4 Fe 20 W 5 DMFA 500 1000 120 2 2967.498 4 Cu 20 W 5 DMFA 500 1000 120 2 502.1629 4 Fe 5 V 20 DMFA 500 1000 120 2 3156.959 4 Cu 5 V 20 DMFA 500 1000 120 2 1254.915 4 Fe 20 V 20 DMFA 500 1000 120 2 3403.2 4 Cu 20 V 20 DMFA 500 1000 120 2 1311.478 4 Fe 5 W 20 DMFA 500 1000 120 2 3215.089 4 Cu 5 W 20 DMFA 500 1000 120 2 801.7368 4 Fe 20 W 20 DMFA 500 1000 120 2 2463.873 4 Cu 20 W 20 DMFA 500 1000 120 2 1286.28 4 Fe 5 V 5 DMAA 500 1000 120 2 3225.547 4 Cu 5 V 5 DMAA 500 1000 120 2 1027.837 4 Fe 20 V 5 DMAA 500 1000 120 2 3455.892 4 Cu 20 V 5 DMAA 500 1000 120 2 1167.907 4 Fe 5 W 5 DMAA 500 1000 120 2 3040.422 4 Cu 5 W 5 DMAA 500 1000 120 2 1625.673 4 Fe 20 W 5 DMAA 500 1000 120 2 2649.228 4 Cu 20 W 5 DMAA 500 1000 120 2 1075.155 4 Fe 5 V 20 DMAA 500 1000 120 2 3454.219 4 Cu 5 V 20 DMAA 500 1000 120 2 1726.461 4 Fe 20 V 20 DMAA 500 1000 120 2 3407.73 4 Cu 20 V 20 DMAA 500 1000 120 2 1391.012 4 Fe 5 W 20 DMAA 500 1000 120 2 3375.964 4 Cu 5 W 20 DMAA 500 1000 120 2 1620.468 4 Fe 20 W 20 DMAA 500 1000 120 2 3347.955 4 Cu 20 W 20 DMAA 500 1000 120 2 1227.624 4 Fe 5 V 5 DMFA 4000 1000 120 2 1285.104 4 Cu 5 V 5 DMFA 4000 1000 120 2 3131.439 4 Fe 20 V 5 DMFA 4000 1000 120 2 1191.938 4 Cu 20 V 5 DMFA 4000 1000 120 2 3019.846 4 Fe 5 W 5 DMFA 4000 1000 120 2 1598.604 4 Cu 5 W 5 DMFA 4000 1000 120 2 3058.827 4 Fe 20 W 5 DMFA 4000 1000 120 2 1111.198 4 Cu 20 W 5 DMFA 4000 1000 120 2 3429.221 4 Fe 5 V 20 DMFA 4000 1000 120 2 1584.459 4 Cu 5 V 20 DMFA 4000 1000 120 2 3624.455 4 Fe 20 V 20 DMFA 4000 1000 120 2 1352.145 4 Cu 20 V 20 DMFA 4000 1000 120 2 3281.384 4 Fe 5 W 20 DMFA 4000 1000 120 2 1323.115 4 Cu 5 W 20 DMFA 4000 1000 120 2 3189.967 4 Fe 20 W 20 DMFA 4000 1000 120 2 1523.089 4 Cu 20 W 20 DMFA 4000 1000 120 2 3211.642 4 Fe 5 V 5 DMAA 4000 1000 120 2 1342.161 4 Cu 5 V 5 DMAA 4000 1000 120 2 3207.565 4 Fe 20 V 5 DMAA 4000 1000 120 2 1494.474 4 Cu 20 V 5 DMAA 4000 1000 120 2 3022.931 5 Cu 20 W 5 DMAA 500 1200 100 1 4260.867 5 Fe 5 V 20 DMAA 500 1200 100 1 1845.083 5 Cu 5 V 20 DMAA 500 1200 100 1 4220.054 5 Fe 20 V 20 DMAA 500 1200 100 1 2422.747 5 Cu 20 V 20 DMAA 500 1200 100 1 4208.349 5 Fe 5 W 20 DMAA 500 1200 100 1 2481.61 5 Cu 5 W 20 DMAA 500 1200 100 1 4414.644 5 Fe 20 W 20 DMAA 500 1200 100 1 2320.681 5 Cu 20 W 20 DMAA 500 1200 100 1 4131.439 5 Fe 5 V 5 DMFA 4000 1200 100 1 3764.029 5 Cu 5 V 5 DMFA 4000 1200 100 1 2456.474 5 Fe 20 V 5 DMFA 4000 1200 100 1 4196.127 5 Cu 20 V 5 DMFA 4000 1200 100 1 2489.818 5 Fe 5 W 5 DMFA 4000 1200 100 1 4326.255 5 Cu 5 W 5 DMFA 4000 1200 100 1 1798.646 5 Fe 20 W 5 DMFA 4000 1200 100 1 4552.989 5 Cu 20 W 5 DMFA 4000 1200 100 1 2438.734 5 Fe 5 V 20 DMFA 4000 1200 100 1 4899.729 5 Cu 5 V 20 DMFA 4000 1200 100 1 1766.201 5 Fe 20 V 20 DMFA 4000 1200 100 1 3853.274 5 Cu 20 V 20 DMFA 4000 1200 100 1 2205.384 5 Fe 5 W 20 DMFA 4000 1200 100 1 4483.398 5 Cu 5 W 20 DMFA 4000 1200 100 1 2193.717 5 Fe 20 W 20 DMFA 4000 1200 100 1 3915.764 5 Cu 20 W 20 DMFA 4000 1200 100 1 2130.307 5 Fe 5 V 5 DMAA 4000 1200 100 1 4268.58 5 Cu 5 V 5 DMAA 4000 1200 100 1 2449.769 5 Fe 20 V 5 DMAA 4000 1200 100 1 4051.658 5 Cu 20 V 5 DMAA 4000 1200 100 1 2319.5 5 Fe 5 W 5 DMAA 4000 1200 100 1 4182.63 5 Cu 5 W 5 DMAA 4000 1200 100 1 1913.637 5 Fe 20 W 5 DMAA 4000 1200 100 1 4171.779 5 Cu 20 W 5 DMAA 4000 1200 100 1 1788.613 6 Fe 5 V 20 DMAA 4000 1200 100 1 4304.112 6 Cu 5 V 20 DMAA 4000 1200 100 1 2340.053 6 Fe 20 V 20 DMAA 4000 1200 100 1 3973.3 6 Cu 20 V 20 DMAA 4000 1200 100 1 2242.964 6 Fe 5 W 20 DMAA 4000 1200 100 1 4220.131 6 Cu 5 W 20 DMAA 4000 1200 100 1 2029.409 6 Fe 20 W 20 DMAA 4000 1200 100 1 4474.279 6 Cu 20 W 20 DMAA 4000 1200 100 1 2185.812 6 Fe 5 V 5 DMFA 500 1200 100 2 3200.736 6 Cu 5 V 5 DMFA 500 1200 100 2 5251.12 6 Fe 20 V 5 DMFA 500 1200 100 2 2941.772 6 Cu 20 V 5 DMFA 500 1200 100 2 5348.456 6 Fe 5 W 5 DMFA 500 1200 100 2 3216.89 6 Cu 5 W 5 DMFA 500 1200 100 2 5601.562 6 Fe 20 W 5 DMFA 500 1200 100 2 3213.059 6 Cu 20 W 5 DMFA 500 1200 100 2 5455.892 6 Fe 5 V 20 DMFA 500 1200 100 2 3248.214 6 Cu 5 V 20 DMFA 500 1200 100 2 4972.636 6 Fe 20 V 20 DMFA 500 1200 100 2 3355.542 6 Cu 20 V 20 DMFA 500 1200 100 2 5019.747 6 Fe 5 W 20 DMFA 500 1200 100 2 3747.147 6 Cu 5 W 20 DMFA 500 1200 100 2 5053.546 6 Fe 20 W 20 DMFA 500 1200 100 2 3082.532 6 Cu 20 W 20 DMFA 500 1200 100 2 5055.11 6 Fe 5 V 5 DMAA 500 1200 100 2 2903.681 6 Cu 5 V 5 DMAA 500 1200 100 2 4726.624 6 Fe 20 V 5 DMAA 500 1200 100 2 3378.448 6 Cu 20 V 5 DMAA 500 1200 100 2 5179.236 6 Fe 5 W 5 DMAA 500 1200 100 2 3013.919 6 Cu 5 W 5 DMAA 500 1200 100 2 4803.361 6 Fe 20 W 5 DMAA 500 1200 100 2 3213.767 6 Cu 20 W 5 DMAA 500 1200 100 2 5545.379 6 Fe 5 V 20 DMAA 500 1200 100 2 3585.461 6 Cu 5 V 20 DMAA 500 1200 100 2 4672.836 6 Fe 20 V 20 DMAA 500 1200 100 2 3238.526 6 Cu 20 V 20 DMAA 500 1200 100 2 5161.146 6 Fe 5 W 20 DMAA 500 1200 100 2 3014.8 7 Cu 20 V 5 DMFA 4000 1200 120 1 3393.315 7 Fe 5 W 5 DMFA 4000 1200 120 1 1403.261 7 Cu 5 W 5 DMFA 4000 1200 120 1 3555.009 7 Fe 20 W 5 DMFA 4000 1200 120 1 1308.279 7 Cu 20 W 5 DMFA 4000 1200 120 1 3512.98 7 Fe 5 V 20 DMFA 4000 1200 120 1 1284.812 7 Cu 5 V 20 DMFA 4000 1200 120 1 3435.316 7 Fe 20 V 20 DMFA 4900 1200 120 1 1694.665 7 Cu 20 V 20 DMFA 4000 1200 120 1 3496.463 7 Fe 5 W 20 DMFA 4000 1200 120 1 1143.947 7 Cu 5 W 20 DMFA 4000 1200 120 1 3456.876 7 Fe 20 W 20 DMFA 4000 1200 120 1 1617.505 7 Cu 20 W 20 DMFA 4000 1200 120 1 3879.49 7 Fe 5 V 5 DMAA 4000 1200 120 1 1273.745 7 Cu 5 V 5 DMAA 4000 1200 120 1 3382.074 7 Fe 20 V 5 DMAA 4000 1200 120 1 881.0287 7 Cu 20 V 5 DMAA 4000 1200 120 1 3104.413 7 Fe 5 W 5 DMAA 4000 1200 120 1 1395.572 7 Cu 5 W 5 DMAA 4000 1200 120 1 3141.805 7 Fe 20 W 5 DMAA 4000 1200 120 1 1774.357 7 Cu 20 W 5 DMAA 4000 1200 120 1 3413.901 8 Fe 5 V 20 DMAA 4000 1200 120 1 1649.139 8 Cu 5 V 20 DMAA 4000 1200 120 1 3368.794 8 Fe 20 V 20 DMAA 4000 1200 120 1 1824.133 8 Cu 20 V 20 DMAA 4000 1200 120 1 3660.883 8 Fe 5 W 20 DMAA 4000 1200 120 1 1179.379 8 Cu 5 W 20 DMAA 4000 1200 120 1 3628.204 8 Fe 20 W 20 DMAA 4000 1200 120 1 1293.674 8 Cu 20 W 20 DMAA 4000 1200 120 1 3019.058 8 Fe 5 V 5 DMFA 500 1200 120 2 2990.086 8 Cu 5 V 5 DMFA 500 1200 120 2 1029.93 8 Fe 20 V 5 DMFA 500 1200 120 2 3062.541 8 Cu 20 V 5 DMFA 500 1200 120 2 1242.527 8 Fe 5 W 5 DMFA 500 1200 120 2 3147.093 8 Cu 5 W 5 DMFA 500 1200 120 2 1316.01 8 Fe 20 W 5 DMFA 500 1200 120 2 3127.044 8 Cu 20 W 5 DMFA 500 1200 120 2 1729.955 8 Fe 5 V 20 DMFA 500 1200 120 2 3923.339 8 Cu 5 V 20 DMFA 500 1200 120 2 1251.202 8 Fe 20 V 20 DMFA 500 1200 120 2 3291.114 8 Cu 20 V 20 DMFA 500 1200 120 2 1309.178 8 Fe 5 W 20 DMFA 500 1200 120 2 3166.405 8 Cu 5 W 20 DMFA 500 1200 120 2 1079.929 8 Fe 20 W 20 DMFA 500 1200 120 2 3399.78 8 Cu 20 W 20 DMFA 500 1200 120 2 1317.061 8 Fe 5 V 5 DMAA 500 1200 120 2 3249.165 8 Cu 5 V 5 DMAA 500 1200 120 2 1310.566 8 Fe 20 V 5 DMAA 500 1200 120 2 3181.768 8 Cu 20 V 5 DMAA 500 1200 120 2 1384.317 8 Fe 5 W 5 DMAA 500 1200 120 2 3483.545 8 Cu 5 W 5 DMAA 500 1200 120 2 1483.464 8 Fe 20 W 5 DMAA 500 1200 120 2 3243.016 8 Cu 20 W 5 DMAA 500 1200 120 2 1659.831 8 Fe 5 V 20 DMAA 500 1200 120 2 3832.087 8 Cu 5 V 20 DMAA 500 1200 120 2 1434.119 8 Fe 20 V 20 DMAA 500 1200 120 2 3898.378 8 Cu 20 V 20 DMAA 500 1200 120 2 1514.125 8 Fe 5 W 20 DMAA 500 1200 120 2 3320.126 8 Cu 5 W 20 DMAA 500 1200 120 2 1269.161 8 Fe 20 W 20 DMAA 500 1200 120 2 3552.422 8 Cu 20 W 20 DMAA 500 1200 120 2 1408.177 8 Fe 5 V 5 DMFA 4000 1200 120 2 1330.367 8 Cu 5 V 5 DMFA 4000 1200 120 2 3233.872 8 Fe 20 V 5 DMFA 4000 1200 120 2 1119.671 8 Cu 20 V 5 DMFA 4000 1200 120 2 3565.294 8 Fe 5 W 5 DMFA 4000 1200 120 2 1540.59 8 Cu 5 W 5 DMFA 4000 1200 120 2 3197.359 8 Fe 20 W 5 DMFA 4000 1200 120 2 1421.148 8 Cu 20 W 5 DMFA 4000 1200 120 2 3467.429 8 Fe 5 V 20 DMFA 4000 1200 120 2 1265.396

In this iteration, each of the metal acetylacetonates, the DMAA, and the DMFA is made up as a stock solution in phenol. An appropriate quantity of each stock solution is then combined using a Hamilton MicroLab 4000 laboratory robot into a single vial for mixing. For example, the stock solutions to produce rows 1, 65, 129, 193, 257, 321, 385, and 449 or TABLE 12, are 0.01 molar Pd (acetylacetonate), 0.01 molar each of Fe (acetylacetonate) and V (acetylacetonate) and 5 molar DMFA. Ten ml of each stock solution is produced by manual weighing and mixing. Aliquots of the stock solutions are measured as follows in TABLE 13. The mixture is stirred using a miniature magnetic stirrer. TABLE 13 0.01 molar Pd(acetylacetonate)  25 microliters 0.01 molar Fe(acetylacetonate) 125 microliters 0.01 molar V(acetylacetonate) 125 microliters   5 molar DMFA  25 microliters Pure Phenol 700 microliters

In the second iteration, pressure chamber reactor 54 is heated and pressurized to the conditions shown as Block 1 in TABLE 7. The procedure described as iteration 1 is repeated in the system described with reference to FIG. 3 and FIG. 4 with the species of TABLE 10. This process is repeated until all the block conditions have been run.

The performance of each vial is given in the column “TON” of TABLE 13. These results are then analyzed using a “General Linear Model” (GLM) routine in Minitab software. A GLM routine performs analysis of variance (ANOVA) on any specified mathematical model potentially describing a relationship between control factors and response. The routine determines which terms of the model actually have a statistically significant influence on response. The GLM routine is set to calculate an Analysis of Variance (ANOVA) for all main effects, 2-way interactions, and 3-way interactions in data. In a factorial design, an effect of a factor is the average change in response when the value of that factor is changed from its low level to its high level. The effect is a main effect when it is calculated without including the influence of other factors. A 2-way interaction mathematically describes change in the effect of one factor when a second factor is changed from its low level to its high level. A 3-way interaction mathematically describes change in the effect of one factor when two other factors simultaneously are changed from respective low levels to respective high levels.

The ANOVA in this Example is given in TABLE 14. TABLE 14 Pressure*CS 1 11954 11954 11954 0.146 0.702 Temperature*Time 1 33291520 33291520 33291520 407.672 0.000 YES Temperature*M1 1 43430 43430 43430 0.532 0.466 Temperature*M2 1 94767 94767 94767 1.160 0.282 Temperature*CS 1 90412 90412 90412 1.107 0.293 Time*M1 1 1491 1491 1491 0.018 0.893 Time*M2 1 93605 93605 93605 1.146 0.285 Time*CS 1 76043 76043 76043 0.931 0.335 M1*M2 1 77799 77799 77799 0.953 0.330 M1*CS 1 169760 169760 169760 2.079 0.150 M2*CS 1 407136 407136 407136 4.986 0.026 M1 amt*M2 amt*CS amt 1 361079 361079 361079 4.422 0.036 M1 amt*M2 amt*Pressure 1 21432 21432 21432 0.262 0.609 M1 amt*M2 amt*Temperature 1 271 271 271 0.003 0.954 M1 amt*M2 amt*Time 1 13991 13991 13991 0.171 0.679 M1 amt*M2 amt*M1 1 281433 281433 281433 3.446 0.064 M1 amt*M2 amt*M2 1 1 1 1 0.000 0.997 M1 amt*M2 amt*CS 1 116073 116073 116073 1.421 0.234 M1 amt*CS amt*Pressure 1 114627 114627 114627 1.404 0.237 M1 amt*CS amt*Temperature 1 466 466 466 0.006 0.940 M1 amt*CS amt*Time 1 69157 69157 69157 0.847 0.358 M1 amt*CS amt*M1 1 164860 164860 164860 2.019 0.156 M1 amt*CS amt*M2 1 14698 14698 14698 0.180 0.672 M1 amt*CS amt*CS 1 334131 334131 334131 4.092 0.044 M1 amt*Pressure*Temperature 1 235 235 235 0.003 0.957 M1 amt*Pressure*Time 1 167809 167809 167809 2.055 0.153 M1 amt*Pressure*M1 1 8172 8172 8172 0.100 0.752 M1 amt*Pressure*M2 1 4377 4377 4377 0.054 0.817 M1 amt*Pressure*CS 1 6356 6356 6356 0.078 0.780 M1 amt*Temperature*Time 1 67161 67161 67161 0.822 0.365 M1 amt*Temperature*M1 1 194664 194664 194664 2.384 0.123 M1 amt*Temperature*M2 1 569 569 569 0.007 0.934 M1 amt*Temperature*CS 1 11 11 11 0.000 0.991 M1 amt*Time*M1 1 6489 6489 6489 0.079 0.778 M1 amt*Time*M2 1 30862 30862 30862 0.378 0.539 Source DF Seq SS Adj SS Adj MS F Ratio P Significant at P < 0.01 M1 amt 1 16412 16412 16412 0.201 0.654 M2 amt 1 77926 77926 77926 0.954 0.329 CS amt 1 33586 33586 33586 0.411 0.522 Pressure 1 4616039 4616039 4016039 56.526 0.000 YES Temperature 1 216802139 216802139 216802139 2654.854 0.000 YES Time 1 31205785 31205785 31205785 382.131 0.000 YES M1 1 22404811 22404811 22404811 274.358 0.000 YES M2 1 182205 182205 182205 2.231 0.136 CS 1 3702 3702 3702 0.045 0.832 M1 amt*M2 amt 1 27036 27036 27036 0.331 0.565 M1 amt*CS amt 1 58292 58292 58292 0.714 0.399 M1 amt*Pressure 1 61467 61467 61467 0.753 0.386 M1 amt*Temperature 1 26926 26926 26926 0.330 0.566 M1 amt*Time 1 110415 110415 110415 1.352 0.246 M1 amt*M1 1 34335 34335 34335 0.420 0.517 M1 amt*M2 1 232680 232680 232680 2.849 0.092 M1 amt*CS 1 260446 260446 260446 3.189 0.075 M2 amt*CS amt 1 79627 79627 79627 0.975 0.324 M2 amt*Pressure 1 341447 341447 341447 4.181 0.042 M2 amt*Temperature 1 477 477 477 0.006 0.939 M2 amt*Time 1 125869 125869 125869 1.541 0.215 M2 amt*M1 1 14190 14190 14190 0.174 0.677 M2 amt*M2 1 81553 81553 81553 0.999 0.318 M2 amt*CS 1 8125 8125 8125 0.099 0.753 CS amt*Pressure 1 33749 33749 33749 0.413 0.521 CS amt*Temperature 1 295416 295416 295416 3.618 0.058 CS amt*Time 1 7438 7438 7438 0.091 0.763 CS amt*M1 1 132568 132568 132568 1.623 0.203 CS amt*M2 1 37280 37280 37280 0.457 0.500 CS amt*CS 1 23702 23702 23702 0.290 0.590 Pressure*Temperature 1 40272 40272 40272 0.493 0.483 Pressure*Time 1 38 38 38 0.000 0.983 Pressure*M1 1 253770 253770 253770 3.108 0.079 Pressure*M2 1 260899 260899 260899 3.195 0.075 M1 amt*Time*CS 1 163612 163612 163612 2.004 0.158 M1 amt*M1*M2 1 77397 77397 77397 0.948 0.331 M1 amt*M1*CS 1 11421 11421 11421 0.140 0.709 M1 amt*M2*CS 1 59409 59409 59409 0.727 0.394 M2 amt*CS amt*Pressure 1 6344 6344 6344 0.078 0.781 M2 amt*CS amt*Temperature 1 0 0 0 0.000 1.000 M2 amt*CS amt*Time 1 70019 70019 70019 0.857 0.355 M2 amt*CS amt*M1 1 89887 89887 89887 1.101 0.295 M2 amt*CS amt*M2 1 120523 120523 120523 1.476 0.225 M2 amt*CS amt*CS 1 8479 8479 8479 0.104 0.747 M2 amt*Pressure*Temperature 1 190090 190090 190090 2.328 0.128 M2 amt*Pressure*Time 1 14716 14716 14716 0.180 0.671 M2 amt*Pressure*M1 1 7373 7373 7373 0.090 0.764 M2 amt*Pressure*M2 1 16357 16357 16357 0.200 0.655 M2 amt*Pressure*CS 1 35027 35027 35027 0.429 0.513 M2 amt*Temperature*Time 1 26831 26831 26831 0.329 0.567 M2 amt*Temperature*M1 1 626 626 626 0.008 0.930 M2 amt*Tempereture*M2 1 94448 94448 94448 1.157 0.283 M2 amt*Temperature*CS 1 1212 1212 1212 0.015 0.903 M2 amt*Time*M1 1 77055 77055 77055 0.944 0.332 M2 amt*Time*M2 1 6233 6233 6233 0.076 0.782 M2 amt*Time*CS 1 337817 337817 337817 4.137 0.043 M2 amt*M1*M2 1 38653 38653 38653 0.473 0.492 M2 amt*M1*CS 1 23751 23751 23751 0.291 0.590 M2 amt*M2*CS 1 3270 3270 3270 0.040 0.842 CS amt*Pressure*Temperature 1 84561 84561 84561 1.035 0.310 CS amt*Pressure*Time 1 212868 212868 212868 2.607 0.107 CS amt*Pressure*M1 1 34495 34495 34495 0.422 0.516 CS amt*Pressure*M2 1 20299 20299 20299 0.249 0.618 CS amt*Pressure*CS 1 12034 12034 12034 0.147 0.701 CS amt*Temperature*Time 1 174636 174636 174636 2.139 0.144 CS amt*Temperature*M1 1 535239896 535239896 535239896 6554.288 0.000 YES CS amt*Temperature*M2 1 4708 4708 4708 0.058 0.810 CS amt*Temperature*CS 1 331 331 331 0.004 0.949 CS amt*Time*M1 1 112874 112874 112874 1.382 0.240 CS amt*Time*M2 1 1469 1469 1469 0.018 0.893 CS amt*Time*CS 1 804 804 804 0.010 0.921 CS amt*M1*M2 1 75785 75785 75785 0.928 0.336 CS amt*M1*CS 1 22036 22036 22036 0.270 0.604 CS amt*M2*CS 1 34743 34743 34743 0.425 0.515 Pressure*Temperature*Time 1 950930 950930 950930 11.645 0.001 YES Pressure*Temperature*M1 1 18226 18226 18226 0.223 0.637 Pressure*Temperature*M2 1 11544 11544 11544 0.141 0.707 Pressure*Temperature*CS 1 67428 67428 67428 0.826 0.364 Pressure*Time*M1 1 310071 310071 310071 3.797 0.052 Pressure*Time*M2 1 10784 10784 10784 0.132 0.717 Pressure*Time*CS 1 2008 2008 2008 0.025 0.875 Pressure*M1*M2 1 12343 12343 12343 0.151 0.698 Pressure*M1*CS 1 14220 14220 14220 0.174 0.677 Pressure*M2*CS 1 67936 67936 67936 0.832 0.362 Temperature*Time*M1 1 221695 221695 221695 2.715 0.100 Temperature*Time*M2 1 38 38 38 0.000 0.983 Temperature*Time*CS 1 10 10 10 0.000 0.991 Temperature*M1*M2 1 24040 24040 24040 0.294 0.588 Temperature*M1*CS 1 257092 257092 257092 3.148 0.077 Temperature*M2*CS 1 848 848 848 0.010 0.919 Time*M1*M2 1 53303 53303 53303 0.653 0.420 Time*M1*CS 1 44080 44080 44080 0.540 0.463 Time*M2*CS 1 7295 7295 7295 0.089 0.765 M1*M2*CS 1 319669 319669 319669 3.915 0.049 Error 382 31195094 31195094 81662.55 Total 511 885328201

The column “Significant at P<0.01” of TABLE 14 defines the factors and interactions in the model, which have a statistically significant effect on the response with a probability of incorrect decision of less than 1%. The column shows that only 5 of the 129 possible main effects, 2-way interactions, and 3-way interactions have a significant effect on the TON. It is noted that a 3-way interaction (CS amt*Temperature*M1) has the largest influence on the TON (FIG. 5).

This Example shows that the disclosed method can perform large numbers of experiments and can sort out variables in a combinatorial experiment to detect key process interactions. From this interaction a favorable condition for obtaining high (>5500) TON is determined as shown in TABLE 15. TABLE 15 Factor Identity Amount M1 Cu Any M2 Any Any CS Any 500 Pressure Any Temperature 100 C. Time 2 hr

The interaction identifies a unique condition in which two formulation variables (M1=Cu and CS amount=500) generate a very high level of TON only when the temperature is at 100° C.

It will be understood that each of the elements described above, or two or more together, may also find utility in applications differing from the types described herein. While the invention has been illustrated and described as embodied in a sequential high-throughput screening method and system, it is not intended to be limited to the details shown, since various modifications and substitutions can be made without departing in any way from the spirit of the present invention. For example, robotic equipment can be used to prepare samples and various types of parallel analytical screening methods can be incorporated. As such, further modifications and equivalents of the invention herein disclosed may occur to persons skilled in the art using no more than routine experimentation, and all such modifications and equivalents are believed to be within the spirit and scope of the invention as defined by the following claims. 

1. A high-throughput screening method, comprising the steps of: (A) sequentially loading a plurality of discrete combinations of reactants into a longitudinal reaction zone; (B) reacting each of said plurality of combinations as each combinations passes through said reaction zone to provide a continuously or an incrementally varying reaction product; and (C) sequentially discharging the reaction product of each of said combinations from said reaction zone as reaction of each of said combinations is completed.
 2. The method of claim 1, wherein the discrete combinations of reactants vary in identity or amount.
 3. The method of claim 1, wherein step (B) comprises subjecting each sequentially loaded combination to a varying reaction parameter within said zone.
 4. The method of claim 1, wherein each combination of reactants is loaded in a vial prior to step (A).
 5. The method of claim 1, wherein said combinations of reactants are suspended in a vapor stream.
 6. The method of claim 2, further comprising the steps of: (D) detecting said varying products and (E) correlating said products with said varying reactants to provide a nonrandom combinatorial library of product.
 7. The method of claim 3, further comprising the steps of: (D) detecting said varying products and (E) correlating said products with said varying reaction parameters to provide a nonrandom combinatorial library of product.
 8. The method of claim 1, further comprising sequentially loading said combinations into an air lock, sealing said air lock and pressurizing said air lock to a pressure substantially equal to a pressure in said reaction zone prior to loading said combinations according to step (A).
 9. The method of claim 1, further comprising sealing an air lock prior to discharge of said reaction product according to said step (C); discharging said reaction product from said reaction zone to said air lock; sealing said air lock from said reaction zone; releasing pressure in said air lock; and discharging said reaction product from said air lock.
 10. The method of claim 1, wherein said combinations of reactants are at least partially embodied in a liquid, said liquid being contacted within said longitudinal reaction zone with a second reactant at least partially embodied in a gas, the second reactant having a mass transfer rate into the liquid sufficient to allow a reaction rate that is essentially independent of said mass transfer rate.
 11. The method of claim 10, wherein said each combination of reactants includes a catalyst system comprising a Group VIII B metal.
 12. The method of claim 11, wherein the Group VIII B metal is palladium.
 13. The method of claim 11, wherein the catalyst system further comprises a halide composition.
 14. The method of claim 11, wherein the catalyst system further comprises an inorganic co-catalyst.
 15. The method of claim 14, wherein the catalyst system further comprises a combination of inorganic co-catalysts.
 16. (canceled)
 17. (canceled)
 18. (canceled)
 19. (canceled)
 20. (canceled)
 21. (canceled)
 22. (canceled)
 23. (canceled)
 24. (canceled)
 25. (canceled)
 26. A high throughput screening method, comprising: (A) selecting a set of reactants; (B) (i) sequentially reacting each member of said set under a selected set of catalyst or reaction conditions according to a reaction parameter to provide continuously or incrementally varying product, and (iii) evaluating a set of products from said reacting step; and (C) reiterating (B) wherein a successive set of catalyst or reaction conditions selected for a step (i) is chosen as a result of an evaluating step (iii) of a preceding iteration of step (B).
 27. The method of claim 26, wherein said each member is reacted in a catalyst system comprising a Group VIII B metal.
 28. The method of claim 26, wherein said each member is reacted in a catalyst system comprising palladium.
 29. The method of claim 26, wherein said each member is reacted in a catalyst system comprising a halide composition.
 30. The method of claim 26, wherein said each member is reacted in a catalyst system that includes an inorganic co-catalyst.
 31. The method of claim 26, wherein said each member is reacted in a catalyst system that includes a combination of inorganic co-catalysts.
 32. The method of claim 26, comprising reiterating (B) until said products are evaluated as satisfactory against a preset standard.
 33. The method of claim 26, comprising reiterating (B) until said products are evaluated as satisfactory by a general linear model analysis routine.
 34. The method of claim 26, comprising reiterating (B) to complete a full factorial design experiment on said set of catalyst or reaction conditions and said set of reactants.
 35. The method of claim 26, comprising reiterating (B) until said evaluating (iii) comprises a complete observation of each of all possible combinations of catalyst or reaction condition.
 36. A method of screening multiple chemical reactions according to reaction variables, comprising steps of: (A) sequentially loading combinations of reactants into a longitudinal reaction zone through a charge valve; (B) subjecting each sequentially loaded combination to a parameter of reaction within said zone to provide continuously or incrementally varying product; and (D) sequentially discharging a reaction product of each of said combination from said reaction zone as reaction of each of said combination is completed.
 37. The method of claim 36, wherein step (A) comprises comprising sequentially loading varying combinations of said reactants into said longitudinal reaction zone.
 38. The method of claim 36, wherein step (B) comprises subjecting each sequentially loaded combination to a varying parameter of reaction within said zone.
 39. The method of claim 36, wherein step (B) comprises subjecting each sequentially loaded combination to a varying parameter of reaction within said zone to provide continuously and incrementally varying product.
 40. The method of claim 36, wherein each said combination of reactants is sequentially loaded in a vial.
 41. The method of claim 36, wherein said varying combinations of reactants are suspended in a vapor stream.
 42. The method of claim 36; further comprising: (E) controlling a composition of each sequentially loaded combination and controlling said varying parameter of reaction within said zone; (F) detecting said varying product; and (G) correlating said detected product with said varying parameters of said reaction to provide a nonrandom combinatorial library of product.
 43. The method of claim 36, further comprising sequentially loading said combinations into an air lock, sealing said air lock and pressurizing said air lock to a pressure substantially equal to a pressure in said reaction zone prior to loading said combinations according to step (A).
 44. The method of claim 36, comprising sealing an air lock prior to discharge of said reaction product according to said step (D), discharging said reaction product from said reaction zone to said air lock; sealing said air lock from said reaction zone, releasing pressure in said air lock and discharging said reaction product from said air lock.
 45. The method of claim 36, comprising providing said combinations of reactants at least partially embodied in a liquid and contacting said liquid within said longitudinal reaction zone with a second reactant system at least partially embodied in a gas, the second reactant system having a mass transport rate into the liquid wherein the liquid forms a film having a thickness sufficient to allow a reaction rate that is essentially independent of the mass transport rate of the second reactant system into the liquid to synthesize said reaction product. 